Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31400 Toulouse, France.
Molecules. 2020 Feb 25;25(5):1030. doi: 10.3390/molecules25051030.
With the advent of structural biology in the drug discovery process, medicinal chemists gained the opportunity to use detailed structural information in order to progress screening hits into leads or drug candidates. X-ray crystallography has proven to be an invaluable tool in this respect, as it is able to provide exquisitely comprehensive structural information about the interaction of a ligand with a pharmacological target. As fragment-based drug discovery emerged in the recent years, X-ray crystallography has also become a powerful screening technology, able to provide structural information on complexes involving low-molecular weight compounds, despite weak binding affinities. Given the low numbers of compounds needed in a fragment library, compared to the hundreds of thousand usually present in drug-like compound libraries, it now becomes feasible to screen a whole fragment library using X-ray crystallography, providing a wealth of structural details that will fuel the fragment to drug process. Here, we review theoretical and practical aspects as well as the pros and cons of using X-ray crystallography in the drug discovery process.
随着结构生物学在药物发现过程中的出现，药物化学家有机会利用详细的结构信息将筛选出的化合物推进到先导化合物或候选药物。X 射线晶体学在这方面已被证明是一种非常宝贵的工具，因为它能够提供关于配体与药理学靶标相互作用的极其全面的结构信息。随着近年来基于片段的药物发现的出现，X 射线晶体学也成为一种强大的筛选技术，能够提供涉及低分子量化合物的复合物的结构信息，尽管它们的结合亲和力较弱。鉴于片段文库中所需的化合物数量较少，与通常存在于类药性化合物文库中的数十万相比，现在可以使用 X 射线晶体学筛选整个片段文库，提供丰富的结构细节，为片段到药物的过程提供动力。在这里，我们综述了在药物发现过程中使用 X 射线晶体学的理论和实际方面以及优缺点。
